PMID- 35353151
OWN - NLM
STAT- MEDLINE
DCOM- 20220401
LR  - 20220817
IS  - 2164-2591 (Electronic)
IS  - 2164-2591 (Linking)
VI  - 11
IP  - 3
DP  - 2022 Mar 2
TI  - Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization 
      and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea.
PG  - 34
LID - 10.1167/tvst.11.3.34 [doi]
LID - 34
AB  - PURPOSE: M1 macrophages can promote corneal allograft rejection (CGR). Inhibiting 
      M1 macrophage polarization by the JAK/STAT1 pathway may be a new strategy to 
      prevent CGR. Tofacitinib, a potent pan-JAK inhibitor, can inhibit JAK/STAT 
      activation. Here, we investigated the inhibitory effects of tofacitinib on M1 
      macrophage polarization and its therapeutic effect on rat CGR. METHODS: Corneal 
      allograft transplantation was performed and administrated with 0.3% tofacitinib 
      in rats. The corneal allografts were assessed clinically. The corneas were 
      detected for M1 macrophages, lymphatic vessels, and inflammatory cytokine 
      expression using immunohistochemistry and real-time polymerase chain reaction 
      (PCR). Dendritic cells (DCs) in ipsilateral cervical lymph nodes were detected by 
      flow cytometry. The effect and mechanism of tofacitinib on macrophages were 
      explored by real-time PCR, enzyme-linked immunoassay, and western blot analysis 
      in vitro. RESULTS: The results showed that topical administration of 0.3% 
      tofacitinib significantly prolonged corneal graft survival. Tofacitinib-treated 
      corneal allografts displayed a proportionate decrease in M1 macrophages and 
      reduced lymphatic vessel density with fewer DCs in rat ipsilateral cervical lymph 
      nodes. Tofacitinib reduced the mRNA expression of inflammatory cytokines, 
      including iNOS, MCP-1, TNF-alpha, IL-6, IL-1beta, and VEGF-C, and inhibited STAT1 
      activation in rat corneal grafts. In addition, tofacitinib suppressed M1 
      macrophage polarization via STAT1 activation after IFN-gamma and lipopolysaccharide 
      stimulation in vitro. CONCLUSIONS: Tofacitinib could suppress M1 macrophage 
      polarization and subsequently delay CGR by inhibiting STAT1 activation. The data 
      indicate that tofacitinib is an effective drug for CGR. TRANSLATIONAL RELEVANCE: 
      This study provided evidence that topical administration of 0.3% tofacitinib may 
      be a novel clinical strategy to prevent CGR.
FAU - Yu, Jianfeng
AU  - Yu J
AD  - Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu 
      Province, China.
AD  - Medical School, Nantong University, Nantong, Jiangsu Province, China.
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, Guangdong Province, China.
FAU - Li, Pengfei
AU  - Li P
AD  - Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu 
      Province, China.
AD  - Medical School, Nantong University, Nantong, Jiangsu Province, China.
FAU - Li, Zhuang
AU  - Li Z
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, Guangdong Province, China.
FAU - Li, Yingqi
AU  - Li Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, Guangdong Province, China.
FAU - Luo, Jiawei
AU  - Luo J
AD  - Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu 
      Province, China.
AD  - Medical School, Nantong University, Nantong, Jiangsu Province, China.
FAU - Su, Wenru
AU  - Su W
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, Guangdong Province, China.
FAU - Liang, Dan
AU  - Liang D
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual 
      Science, Guangzhou, Guangdong Province, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transl Vis Sci Technol
JT  - Translational vision science & technology
JID - 101595919
RN  - 0 (Piperidines)
RN  - 0 (Pyrimidines)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (Stat1 protein, rat)
RN  - 87LA6FU830 (tofacitinib)
SB  - IM
EIN - Transl Vis Sci Technol. 2022 Aug 1;11(8):15. PMID: 35976658
MH  - Administration, Topical
MH  - Allografts/metabolism
MH  - Animals
MH  - *Cornea/metabolism
MH  - *Macrophages/metabolism
MH  - Piperidines
MH  - Pyrimidines
MH  - Rats
MH  - STAT1 Transcription Factor/genetics/metabolism/pharmacology
PMC - PMC8976928
COIS- Disclosure: J. Yu, None; P. Li, None; Z. Li, None; Y. Li, None; J. Luo, None; W. 
      Su, None; D. Liang, None
EDAT- 2022/03/31 06:00
MHDA- 2022/04/02 06:00
PMCR- 2022/03/30
CRDT- 2022/03/30 12:14
PHST- 2022/03/30 12:14 [entrez]
PHST- 2022/03/31 06:00 [pubmed]
PHST- 2022/04/02 06:00 [medline]
PHST- 2022/03/30 00:00 [pmc-release]
AID - 2778716 [pii]
AID - TVST-21-4370 [pii]
AID - 10.1167/tvst.11.3.34 [doi]
PST - ppublish
SO  - Transl Vis Sci Technol. 2022 Mar 2;11(3):34. doi: 10.1167/tvst.11.3.34.